Expert Review of Clinical Pharmacology最新文献

Introduction: The therapeutic implications of phosphodiesterase (PDE) inhibitors have attracted interest because PDEs are regarded as an intracellular target to be exploited for therapeutic advancements in the treatment of COPD. At present, the only approved approach for the treatment of COPD with PDE inhibitors is the use of an oral PDE4 inhibitor. However, this treatment is not widely employed, primarily due to the narrow therapeutic index associated with oral PDE4 inhibitors, which significantly limits the tolerable dose. The inhalation route represents a viable alternative to the oral route for improving the therapeutic index of PDE4 inhibitors.

Areas covered: The development of inhaled PDE4 inhibitors, with a focus on tanimilast and ensifentrine, the latter of which is a dual PDE3/PDE4 inhibitor.

Expert opinion: The inhalation route offers several advantages regarding the delivery of PDE inhibitors for the management of COPD. Tanimilast and ensifentrine have been shown to improve lung function, reduce exacerbations and enhance quality of life in COPD patients. However, it has not yet been determined which type of COPD patient might benefit more from inhaled PDE4 inhibitors, and it remains unclear whether concomitant inhibition of PDE3 and PDE4 confers a significant benefit compared to blocking PDE4 alone in COPD.

Introduction: Identification and monitoring of adverse drug reactions (ADRs) and interventions to reduce ADRs are essential for patient safety in hospitals. Causality analysis (CA) is an approach that helps to determine a causal link between medication and patient harm (i.e. an ADR). While numerous CA tools exist, there is no gold standard.

Areas covered: Five online databases were searched to identify studies that evaluated the potential clinical utility of CA tools for ADRs. CA tools were mapped against the Bradford Hill (BH) criteria and included if they adhered to the first seven criteria proposed by BH. Upon the database search, 550 studies were identified, with 41 studies being selected that looked at tools mapped to BH. Thirty-four different CA tools were identified in the included studies.

Expert opinion: Naranjo and WHO-UMC were the most reported CA tools for studies examining inter-rater and intra-rater reliability. Naranjo commonly received a 'fair' agreement level while WHO-UMC received a 'substantial' agreement level between raters. Along with kappa statistics, time using the CA tool was also analyzed, with WHO-UMC being the most time-efficient. There does not appear to be one CA tool that can be applied universally to pharmacovigilance efforts in hospital in-patient settings.

Introduction: Atopic dermatitis (AD) is diagnosed based on clinical signs and symptoms as well as on a clinical course lacking distinct laboratory or histological features; however, the recent appearance of molecularly targeted drugs against AD urges us to try to discover and develop biomarkers useful for treating AD patients.

Areas covered: This article commenced with a targeted PubMed search using 'atopic dermatitis' and 'biomarker' as keywords. We combined the findings from the B-PAD study that we have recently published and summarized data, particularly those recently published.

Expert opinion: Many cells and molecules are listed as potential biomarkers of AD, most of which are type 2 mediators. Among them, CCL17/TARC is now thought to be the most reliable biomarker of AD. During the B-PAD study, we recently found that three biomarkers - squamous cell carcinoma antigen 2 (SCCA2), CCL26/eotaxin-3, and lactose dehydrogenase (LDH) - are better able than CCL17/TARC to assess the clinical severity and disease activity of AD. Moreover, although several biomarkers showed good ability to monitor the efficacy of molecularly targeted drugs against AD. More studies on the discovery and development of biomarkers of AD are awaited to refine treatments for AD patients.

Introduction: ANCA-associated vasculitis (AAV) is a rare, life-threatening disease which may result in serious pulmonary and kidney damage. Cyclophosphamide or rituximab and high-dose glucocorticoids significantly improved patient outcomes, but at the expense of severe complications. Moreover, many patients still relapse and bear a significant burden of both disease- and treatment-related complications. Alternative complement pathway and C5a receptor signaling were demonstrated to play an important role in AAV pathogenesis. Avacopan is selective C5a receptor inhibitor successfully tested in renal AAV as glucocorticoid-sparing agent.

Areas covered: Pharmacokinetic/pharmacodynamic properties, clinical efficacy and safety of avacopan, available clinical trials and real-world experience with avacopan.

Expert opinion: In the phase 3 trial avacopan was shown to be non-inferior at six and superior at 12 months compared to high-dose glucocorticoids and either cyclophosphamide or rituximab in patients with active AAV. Treatment with avacopan was well tolerated and associated with improved quality of life. In patients with severe renal AAV, renal function improved more in avacopan-treated than in high-dose glucocorticoid-treated patients. Avacopan could thus replace high-dose glucocorticoids to avoid glucocorticoid-related toxicity and to improve long term renal outcome. As avacopan is CYP 3A4 inhibitor and substrate, drug-drug interactions must be considered during the treatment.

Introduction: Immune checkpoint inhibitors (ICIs) have advanced the treatment of metastatic melanoma by blocking immune system down-regulators enhancing T-cell-mediated anti-tumor responses. However, many ICIs induce immune-related adverse effects (irAEs) that can impact many organ systems.

Areas covered: Strategies used to manage irAEs include corticosteroids, anti-tumor necrosis factor alpha (TNF-α) agents, other biological therapies, fecal microbiota transplantation (FMT), and emerging regimens. In this review, we describe current evidence for the efficacy of ICIs, acute and chronic immune toxicities, and strategies to manage toxicities for patients treated with ICIs.

Expert opinion: IrAE management will likely evolve by developing more tailored approaches to prevent toxicities, improving non-steroidal management strategies and tailoring the dose of steroids, and identifying biomarkers of severe toxicities.

Introduction: The discovery of the role of the calcitonin gene-related peptide (CGPR) in migraine pathogenesis ushered in a new era in headache medicine. This evidence led to the development of small-molecule CGRP receptor antagonists and monoclonal antibodies targeting either CGRP or its receptor.

Areas covered: We will present selected aspects of the role of CGRP in the pathogenesis of migraine, the efficacy of CGRP-targeted treatment, and the still-open questions regarding the practical application of CGRP antagonists in headache medicine.

Expert opinion: CGRP-targeting drugs represent a transformative approach to migraine treatment, offering superior efficacy and tolerability compared to traditional therapies, they are a helpful addition to the treatment arsenal but also have their flaws and require further observation. Their availability provides new hope for migraine patients, particularly those who have not responded adequately to conventional treatments. Future directions for migraine care planning, especially for chronic migraine and medication-overuse headache, should include universal access to these specific and effective forms of therapy to prevent complications from the disease and its negative effects in many aspects of a patient's life.

Introduction: Mixed hyperlipidemia represents a substantial public health issue and a considerable burden on healthcare systems. Although the introduction of statins and LDL-cholesterol lowering agents have significantly reduced the incidence of atherosclerotic cardiovascular diseases (ASCVD), a significant portion of the population continues to exhibit ASCVD progression due to elevated triglyceride-rich lipoprotein (TRL) levels. This persistent risk has catalyzed the development of novel pharmacological interventions targeting these lipoproteins.

Areas covered: Our special report commenced with a targeted PubMed search using keywords such as 'plozasiran,' 'zodasiran,' and terms related to APOC3 and ANGPTL3. As the review progressed, emergent research questions guided further searches, allowing for the inclusion of additional relevant articles to comprehensively illustrate the linkage between TRLs and cardiovascular disease, discuss the roles of APOC3, ANGPTL3, and the pharmaceutical agents that target these proteins, and provide a comparison on the ARCHES-2 and MUIR trials.

Expert opinion: The ARCHES-2 and MUIR trials demonstrated effective triglyceride reduction by these therapies, yet it is uncertain if this correlates with significant clinical benefits. Advances in antisense oligonucleotide technology, especially the GalNAc delivery platform, show promise for personalized lipid management, though challenges such as cost and safety concerns remain.